A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer

• Published in: Clinical cancer research Vol. 12; no. 20; pp. 6106 - 6115
• Main Authors: KERSHAW, Michael H, WESTWARD, Jennifer A, CHEN, Clara C, YANG, James C, ROSENBERG, Steven A, HWU, Patrick, PARKER, Linda L, GANG WANG, ESHHAR, Zelig, MAVROUKAKIS, Sharon A, WHITE, Donald E, WUNDERLICH, John R, CANEVARI, Silvana, ROGERS-FREEZER, Linda
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2006
• Subjects: Antineoplastic agents; Biological and medical sciences; Cellular immunotherapy; Clinical Immunology/Biological Therapy; Cohort Studies; DNA Primers; Experimental Gene Therapy; Female; Female genital diseases; Gynecological cancers: ovarian; Gynecology. Andrology. Obstetrics; Humans; Immune responses to cancer; Immunotherapy, Adoptive - adverse effects; Lymphocyte Transfusion - adverse effects; Medical sciences; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Ovarian Neoplasms - therapy; Patient Selection; Pharmacology. Drug treatments; Polymerase Chain Reaction; T-Lymphocytes - transplantation; Transplantation, Homologous; Tumors; Human; Ovarian diseases; Treatment; Gene; Ovary cancer; T-Lymphocyte; Phase I trial; Genetics; Malignant tumor; Adoptive immunization; Tumor cell; Female genital diseases
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-1183

Purpose: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer. Experimental Design: T cells with reactivity against the ovarian cancer–associated antigen α-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor γ chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells. Results: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111 In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR + tumor cells. Conclusions: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.